title: Preparation, characterization and in vitro efficacy of albumin conjugates of doxorubicin.
abstract: One strategy for improving the antitumor selectivity and toxicity profile of antitumor agents is to design drug carrier systems with suitable transport proteins. Thus, four maleimide derivatives of doxorubicin were bound to thiolated human serum albumin which differed in the stability of the chemical link between drug and spacer. In the maleimide derivatives, 3-maleimidobenzoic or 4-maleimidophenylacetic acid was bound to the 3'-amino position of doxorubicin through a benzoyl or phenylacetyl amide bond and 3-maleimidobenzoic acid hydrazide or 4-maleimidophenylacetic acid hydrazide was bound to the 13-keto position through a benzoyl hydrazone or phenylacetyl hydrazone bond. The acid-sensitive albumin conjugates prepared with the carboxylic hydrazone doxorubicin derivatives exhibited an inhibitory efficacy in the MDA-MB-468 breast cancer cell line and U937 leukemia cell line comparable with that of the free drug (using the BrdU-(5-bromo-2'-deoxyuridine)-incorporation assay and tritiated thymidine incorporation assay respectively, IC50 approximately 0.1-1 microM) whereas conjugates with the amide derivatives showed no or only marginal activity. These results demonstrate that antiproliferative activity depends on the nature of the chemical bond between doxorubicin and carrier protein. Acid-sensitive albumin conjugates are suitable candidates for further in vitro and in vivo assessment.
authors.affiliation: Tumor Biology Center, Department of Medical Oncology, Clinical Research, Freiburg, Federal Republic of Germany.
authors.forename: F
authors.initials: F
authors.lastname: Kratz
authors.forename: U
authors.initials: U
authors.lastname: Beyer
authors.forename: P
authors.initials: P
authors.lastname: Collery
authors.forename: F
authors.initials: F
authors.lastname: Lechenault
authors.forename: A
authors.initials: A
authors.lastname: Cazabat
authors.forename: P
authors.initials: P
authors.lastname: Schumacher
authors.forename: U
authors.initials: U
authors.lastname: Falken
authors.forename: C
authors.initials: C
authors.lastname: Unger
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D001973:Bromodeoxyuridine / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007942:Leukemia, Experimental / Q000188:drug therapy; D008301:Maleimides / Q000737:chemistry; D012709:Serum Albumin / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D008301:Maleimides; D012709:Serum Albumin; D004317:Doxorubicin; D001973:Bromodeoxyuridine; D013936:Thymidine